title: Myo-InositolTrisPyroPhosphate treatment leads to HIF-1α suppression and eradication of early hepatoma tumors in rats.
abstract: Myo-inositol trispyrophosphate (ITPP), a synthetic allosteric effector of hemoglobin, increases the regulated oxygen-releasing capacity of red blood cells (RBCs), leading to suppression of hypoxia-inducible factor 1α (HIF-1α) and to down-regulation of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF). As a consequence, tumor growth is markedly affected. The effect of weekly intravenous injection of ITPP on an orthotopic, syngenic rat hepatocellular carcinoma (HCC) model was compared to that for untreated animals and animals subjected to conventional Doxorubicin chemotherapy. The longitudinal examination of HCC was performed by microCT imaging, and the cellular and molecular changes were evaluated by histology and Western blotting analysis of HIF-1α, VEGF, and caspase-3 gene expression in the tumor and in the surrounding liver. Hematologic impact was evaluated by blood cell-count measurement and determination of P50 (oxygen partial pressure for a 50 % oxygen saturation of hemoglobin). The HCC evaluation by microCT revealed a high potency of ITPP for tumor growth inhibition, thus allowing long-term survival and even cure of almost all the treated animals. The P50 value of hemoglobin in RBCs underwent a shift of 30 % following ITPP injection. Under these conditions, HIF-1α activity was strongly decreased, VEGF expression was down-regulated, and apoptosis was induced in HCC and surrounding liver cells, as indicated by Caspase-3 expression. ITPP did not affect hematologic parameters during treatment. The observations of in vivo tumor eradication suggest a significant clinical potential for ITPP in cancer therapy.
authors.affiliation: Institut National pour Santé et Recherche Médicale, Unit 701, IRCAD Strasbourg, France. marc.aprahamian@ircad.u-strasbg.fr
authors.forename: Marc
authors.initials: M
authors.lastname: Aprahamian
authors.forename: Gaétan
authors.initials: G
authors.lastname: Bour
authors.forename: Chérif Y
authors.initials: CY
authors.lastname: Akladios
authors.forename: Konstantina
authors.initials: K
authors.lastname: Fylaktakidou
authors.forename: Ruth
authors.initials: R
authors.lastname: Greferath
authors.forename: Luc
authors.initials: L
authors.lastname: Soler
authors.forename: Jacques
authors.initials: J
authors.lastname: Marescaux
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lehn
authors.forename: Claude
authors.initials: C
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007295:Inositol Phosphates / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007295:Inositol Phosphates; D042461:Vascular Endothelial Growth Factor A; C516441:inositol trispyrophosphate; D010100:Oxygen